OVERALL DESCRIPTION (Adapted from the application): Among the most devastating disorders of aging are dementing diseases. Prion diseases are age-dependent, degenerative, neurological illnesses and are the focus of this proposal. Much evidence argues that prion diseases are disorders of protein conformation. The emphasis of this project is to investigate the molecular mechanisms that feature not only in the replication of prions but also in the pathogenesis of the disease process: Within this context, the applicants propose to search for compounds that prevent the interaction of PrPc with protein X, which seems to be the rate limiting step of prion formation (Project 1). Synthetic PrP peptides of approximately 60 residues will be studied with respect to their ability to induce neurodegeneration in transgenic (Tg) mice; this process has been shown to depend on the beta-sheet conformation of the peptide. Solid state NMR will be used to determine the structures of aggregated PrP peptides that induce disease. These studies of PrP peptides will be performed in parallel with studies of the Sup35 protein and peptides will be performed in parallel with studies of the Sup35 protein and its N- terminal prion domain in yeast. Such investigations allow them to apply facile tools of yeast genetics to studies of neurodegeneration in humans. Whether distinct conformers of the 60-mer PrP peptides can be created that induce different patterns of neurodegenerative disease is unknown. However, an enlarging body of data argues that strains of prions do produce different patterns of neurodegeneration representing conformational variations in PrPsc. Using a conformation-dependent immunoassay (CDI), Tg mice expressing unglycosylated PrP and mice with inducible transgene expression, they plan to determine if Asn-linked sugar chains modify the properties of prion clearance, which seem to dictate the length of the incubation time. How modifications of Asn-liked sugar chairs affect the neuropathology of experimental prion disease in Tg mice will be assessed. Additionally, neuropathologic changes will be measured as a function of different rates of prion clearance from the CNS in Tg mice with inducible transgenes. The diverse skills, talents and backgrounds of the investigators in the proposed program offer an unusual opportunity to define the molecular mechanisms responsible for neurodegeneration disorders, afflicting older people, including Alzheimer's disease.